ABSTRACT Cockroach allergen exposure elicits cockroach sensitization and poses an increased risk for asthma. However, there are no specific treatments or prophylactic approaches to target cockroach allergen-induced allergy and asthma. We have discovered an important link between C-type lectin receptors (CLRs) and cockroach allergen- induced allergic sensitization and asthma. Dendritic cell immuno-receptor (DCIR) is a CLR expressed mainly in dendritic cells (DCs) that has a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail. DCIR is the only classical CLR with an ITIM that mediates either inhibitory or active signaling. Based on its structural characteristics, DCIR is critical in carbohydrate recognition and ITIM signaling cascades. However, the functional role of DCIR in antigen binding and downstream ITIM signaling-mediated immune responses is still poorly characterized. Recent studies suggest that DCIR is required to modulate lung inflammation and bacterial burden in tuberculosis. We have also demonstrated for the first time that DCIR is highly expressed in basophils and mediates cockroach allergen uptake. On the other hand, we have recently made intriguing findings that mast cells are increased in the lung tissues of cockroach allergen-induced mouse model of asthma and mast cell deficient mice (KitW-sh/W-sh) showed attenuated lung inflammation, highlighting the functional significance of mast cells in the development of asthma. This proposal focuses on mast cells and tests our novel hypothesis that DCIR recognizes cockroach allergen, modulates mast cell activation, and plays a critical role in mast cell-mediated allergic inflammation in allergic asthma. Indeed, we have found a significant binding of cockroach allergen to human DCIR, and cockroach allergen can promote DCIR expression in mast cells and induce mast cell activation with increased release of ?- hexosaminidase and IL-13. Importantly, there was an increased DCIR expression in lung tissue mast cells of mouse model of asthma. These exciting data set the stage to critically evaluate the functional significance of DCIR in the cockroach allergen-induced mast cell activation and mast cell-mediated allergic inflammation in allergic asthma. Aim 1 proposes experiments to determine the relationship between DCIR and asthma by detecting DCIR expression in human lung tissues and plasma of asthmatic patients and healthy subjects. Aim 2 proposes studies to understand the role of DCIR in cockroach allergen binding, uptake, and regulation of cockroach allergen-induced mast cell activation [e.g., degranulation, histamine release, cytokine production, reactive oxygen species (ROS), and intracellular calcium [Ca2+]i ]. Aim 3 proposes experiments to define the role of DCIR in cockroach allergen-induced mouse model of asthma using Dcir-/- mice, or examine the role of DCIR specifically in mast cells in allergic asthma using mast cell deficient mice KitW-sh/W-sh reconstituted with mast cells from WT or Dcir-/- mice. This will lead to subsequent studies to probe the mechanisms underlying the allergen- induced and DCIR-mediated lung inflammation with DCIR as a potential therapeutic target for asthma.